PB2129: THE MODAKAFUSP ALFA IINNOVATE CLINICAL DEVELOPMENT PROGRAM: RATIONALE AND DESIGN OF 3 PHASE 1/2 TRIALS OF AN INNATE IMMUNITY ENHANCER FOR MULTIPLE MYELOMA (MM)
Authors: Sarah A. Holstein, Hira Mian, Cyrille Touzeau, Edwin Kingsley, Dan Vogl, Richard Zuniga, Kaveri Suryanarayan, Shining Wang, Laura Thesillat-Versmee, Yuyin Liu, Tian Chen, Yefei Zhang, Xavier Parot, Hans C. Lee
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: There is an unmet need for novel, targeted therapies for MM that are well tolerated and efficacious, particularly for patients (pts) who have been exposed and may be refractory to multiple drug classes. Modakafusp alfa (moda) is a first-in-class innate immunity enhancer designed to deliver attenuated interferon (IFN) specifically to innate and adaptive immune cells and myeloma cells. Induction of IFN signaling activates innate and adaptive immune cells and induces direct anti-proliferative and apoptotic effects in myeloma cells. Moda comprises two IFN-α2b molecules fused to an anti-CD38 IgG4 mAb, which binds to a unique epitope. The IgG4 backbone has limited effector function, in contrast to the IgG1 backbones of currently approved anti-CD38 mAbs. Preclinical xenograft studies have shown robust anti-tumor effect when moda is combined with standard-of-care agents (SOC), such as IMiDs, PIs, and anti-CD38 mAb, as demonstrated by prolonged tumor growth delays. Moda and daratumumab (dara) may have complementary MoAs, as they do not compete for binding to CD38, and moda has been shown to increase CD38 expression on the surface of immune and myeloma cells. In the first-in-human study in pts with heavily pre-treated RRMM (NCT03215030; Parts 1 and 2), moda given at 1.5 mg/kg Q4W resulted in a manageable safety profile and single-agent activity with an overall response rate (ORR) of 43%; the maximum tolerated dose was 3 mg/kg Q4W. Based on these promising data, moda is being further investigated in 3 ongoing trials in different MM populations. Aims: To present the design of 3 ongoing global, multicentre, open-label trials of moda in pts with MM. Methods: iinnovate-1 (NCT03215030; Figure) is a phase 2, randomized extension study comparing moda 120 mg vs 240 mg Q4W (fixed weight dose equivalents to 1.5 mg/kg and 3 mg/kg) to define the single-agent dose with the optimal benefit/risk profile in pts with ≥3 prior lines of therapy and who are at least triple-class refractory (to an IMiD, a PI, and an anti-CD38 mAb). The primary endpoint is ORR. iinnovate-2 (NCT05556616) is a phase 1b, 3-group study to evaluate the safety and tolerability of moda as part of combination therapy with SOC agents in pts with NDMM (group 1) or RRMM (groups 2 and 3; Figure). In all 3 groups, moda will be escalated/de-escalated as part of doublet or triplet therapy. In group 1, moda will be combined with lenalidomide as post-ASCT maintenance therapy. In group 2, pts will receive moda as part of a doublet. Group 3 will follow on from group 2; pts will receive moda as part of a triplet at a starting dose guided by data from group 2 and the iinnovate-3 study. The primary endpoint for all 3 groups is safety. iinnovate-3 (NCT05590377) is a phase 1/2a study to evaluate the safety, tolerability, and preliminary efficacy of moda in combination with dara SC. The phase 1 dose escalation will enroll pts who have had ≥3 prior lines including an IMiD, a PI, and an anti-CD38 mAb (or are triple-class refractory regardless of prior number of lines; Figure). Two dose levels of moda in combination with dara will be selected for phase 2a optimal dose finding in pts who have received 1–3 prior lines and are refractory to lenalidomide and sensitive (non-refractory) or naïve to an anti-CD38 mAb. The primary endpoint is safety for phase 1, and ORR for phase 2a. Results: n/a Summary/Conclusion: The iinnovate-1-2-3 studies plan to determine the optimal dose of moda as a single agent and in doublet and triplet combinations with SOC agents for different MM pt populations, including pts with the highest unmet medical needs.Keywords: Interferon alpha, Multiple myeloma, Innate Immunity, Cancer immunotherapy